MTORC1 inhibition blocks the gut-homing phenotype induced by retinoic acid in naturally-occurring Treg but not in conventional CD4+ T cells (P6260)

Abstract

Abstract The vitamin A metabolite all-trans retinoic acid (ATRA) is known to induce a gut-homing phenotype in T cells by upregulating the integrin α4β7 and CCR9. We report that, unlike conventional CD4+ T cells, only about half of naturally-occurring Treg (nTreg) upregulate CCR9 in response to ATRA. The bimodal distribution of CCR9+ versus CCR9- Treg subsets was not due to differences in the extent of proliferation, intensity level of FoxP3, or expression of the nTreg/iTreg discriminator Helios. Furthermore, we found that addition of the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented the appearance of the CCR9+ subset of nTreg, but did not prevent CCR9 upregulation by T cells, suggesting nTreg-specific involvement of mTOR in regulation of the expression of CCR9. mTOR involvement was independent of Akt activity, as inhibition of Akt or its downstream target GSK-3β did not prevent CCR9 expression. Additionally, Rictor-/- Treg (which lack mTORC2) showed no diminution of the CCR9+ subset compared to wild-type controls, demonstrating selective participation of mTORC1. These results suggest that nTreg are a heterogeneous population with two subsets: one that does not upregulate CCR9 in response to ATRA, and one that does upregulate CCR9 in an mTORC1-dependent fashion. These findings reveal a novel difference between nTreg and conventional T cells, and provide a framework for which the migratory behavior of nTreg versus T cells may be differentially influenced.